KR100586350B1 - Thermodynamically Stable Form of R-3-[[4-Fluorophenylsulphonyl]amino]-1,2,3,4-tetrahydro-9H-carbazole-9-propanoic Acid Ramatroban - Google Patents

Abstract

The present invention is directed to thermodynamically stable modifications of ramatlovan, the active compounds of formula (I). Thermodynamically stable forms are prepared by melting the metastable form followed by recrystallization, or by inoculating a solution of the metastable active compound with a seed crystal in a thermodynamically stable form. Thermodynamically stable active compounds can be used as agents for asthma.

Ramatlovan, thromboxane A2 antagonist.

Description

Thermodynamically Stable of (R) -3-[[(4-fluorophenyl) sulfonyl] amino] -1,2,3,4-tetrahydro-9H-carbazole-9-propanoic acid (ramatiroban) Form {Thermodynamically Stable Form of (R) -3-[[(4-Fluorophenyl) sulphonyl] amino] -1,2,3,4-tetrahydro-9H-carbazole-9-propanoic Acid (Ramatroban)}

FIELD OF THE INVENTION The present invention relates to novel forms of ramatrobane which are thermodynamically stable at room temperature, methods for their preparation, pharmaceuticals comprising these forms, and their use in the inhibition of diseases.

The preparation of ramatrobane and its use as thromboxane A2 antagonist are already disclosed in EP 242 518.

In the manner disclosed in this document, Lamatrovan was obtained in crystalline modification, referred to as variant II below. Variant II has a melting point of 137 ° C., a melt enthalpy of 80 J / g (DSC, heating rate 2 K / min), characteristic X-ray diffraction, IR spectrum, ¹³ C-solid NMR spectrum, FIR spectrum, and Raman spectrum Is the same as FIGS. 1 to 6. It has now been found that Variant II is metastable and therefore not suitable for use in pharmaceutical formulations such as solid and semi-solid preparations.

Surprisingly, the second variant of Ramatrovan is thermodynamically stable and can be stably stored even after suspension processing, thus suspending the active compounds as well as pharmaceutical formulations, such as suspensions or creams, for example aqueous granulation or wetting. It has been found to be particularly suitable for use in other formulations prepared by grinding. This new variant is referred to as variant I below. The present invention also relates to pharmaceutical formulations containing Ramatroban in the modified I state as the active substance. This formulation may comprise one or more pharmaceutically acceptable auxiliaries such as binders, solvents, fillers and the like.

J. Halbelian, W. McCrowne, J. Pharm. Sci. 58 (1969) 911, and J.-O. Henck et al., Pharm. Ind. 59 (1997) 165-169 describes that stable forms can be obtained when thermodynamically metastable multi-form forms are used in solid and semi-solid formulations such as tablets, suspensions, ointments and the like. In this regard, undesired crystal growth, changes in bioavailability, caking and the like are observed. The two crystal strains of Ramatroban differ in solubility by 60% at room temperature. According to the invention, using the stable strain I, no change in solubility occurs as a result of the conversion. This increases the stability of the Lamatrovan formulation, reducing the risk for patients.

Compared to variant II, variant I clearly distinguishes DSC thermal analysis, X-ray diffraction, ¹³ C-solid NMR spectrum, FIR spectrum and Raman spectrum (FIGS. 1-6). The melting point of variant I is 151 ° C. and the melt enthalpy is 87 J / g.

DSC and TGA thermograms were obtained using DSC 7 and TGA 7 from Perkin-Elmer. X-ray diffractograms were recorded with a Stoe transmission diffractometer. IR, FIR and Raman spectra were recorded using Bruker's Fourier IR spectrometers IFS 66 (IR), IFS 66v (FIR) and IFS 88 (Raman). ¹³ C-solid NMR spectra were recorded using Bruker's MSL 300.

Crystal modifications of Ramatroban are used in pharmaceutical formulations with high purity. For reasons of stability, variant I should not include variant II in relatively large amounts. Preference is given to active compound grades which have a variant II of 10% or less, more particularly preferably 5% or less.

Variant I is particularly preferably Variant I, suspended in water or an inert substance such as a lower alcohol, ketone or alkane, and then transformed to the desired degree by seeding the latamavan of variant II and seeding with the crystals of variant I. Prepared by stirring until quantitative conversion. In general, this conversion takes place at 20 to 50 ° C, preferably at 40 ° C. The resulting crystals of variant I are separated to remove the solvent present and dried at room temperature or at elevated temperature in vacuo until a constant weight is maintained.

In order to produce the required seed crystals, the active compounds are completely dissolved and then quickly cooled to room temperature. The amorphous of the active compound thus obtained is suspended in an inert solvent at room temperature and stirred until complete conversion to thermodynamically stable crystal strain. The residue is filtered and dried in vacuo until constant mass.

<Example 1>

Preparation of Seed Crystals from Melt

About 300 mg of Lamatroban of Variant II was completely melted and then quickly cooled to room temperature. Amorphous material was suspended in 5 ml of ethanol / water (1: 1) and the suspension was stirred at rt for 24 h. After stirring, the suspension was filtered and the residue was dried in vacuo at room temperature.

<Example 2>

Inoculation method

130 g of Ramatrovan (variant II) was dissolved in 650 g of n-butyl acetate and 15 g of water at about 40 ° C. 175 g of solvent were distilled off under vacuum at 40-45 ° C. This solution was then inoculated with 1 g of Ramatrovan (Variation I), and further 300 g of solvent were distilled off at 40-45 ° C. vacuum. The resulting crystal suspension was cooled to room temperature and stirred for several hours. Suction filtered, washed with n-butyl acetate and methyl tert-butyl ether and dried at 50 ° C. vacuum. About 100 g of Lamatrovan (variant I) was obtained.

<Example 3>

Precipitation method

75 g of Ramatrovan (variant II) was dissolved in 135 g of ethyl acetate with warming. 85 g of petroleum ether (35/60) was added dropwise at about 40 ° C. and this batch was inoculated with 1 g of Ramatroban (Variation I). The mixture was stirred at 40 ° C. for about 2-3 hours and cooled to room temperature. An additional 130 g of petroleum ether (35/60) was added to this suspension and stirred for an additional about 5 hours at room temperature. Suction filtered, washed with 100 g of petroleum ether (35/60) and dried at 50 ° C. vacuum. About 65 g of Lamatrovan (variant I) was obtained.

<Example 4>

Conversion in suspension 1

50 g of Ramatrovan (Variation II) was suspended in 75 g of n-butyl acetate and mixed with 0.5 g of Lamatrovan (Variation I). The mixture was stirred at rt for about 100 h. Then it was suction filtered, washed with methyl tert-butyl ether and dried at 50 ° C. vacuum. About 40 g of Lamatrovan (variant I) was obtained.

Example 5

Conversion in suspension 2

About 0.5 g of a mixture of variants I and II (mix ratio-about 1: 1) was suspended in 8 ml of n-heptane and refluxed at about 80 ° C. After one week, the suspension was filtered and the residue was dried in vacuo at room temperature for one day.

<Example 6>

Manufacture of tablets

4590 g of modified I fine Ramatroban was dispersed with a homogenizer with 9180 g of aqueous HPC-L (367 g) and filtered through a 355 im mesh width sieve. Granules were reacted in a granulator with 13,500 g of a premixed and preheated aqueous solution comprising 3162 g of lactose, 4860 g of HPC-L, and 540 g of HPC-M. The resulting granules were dried at 65 ° C. Thereafter, compression was performed in a rotary compactor to obtain a tablet having a diameter of 9.0 mm.

Differential scanning calorimetry Variant I Variant II Melting point 151 137 Melt enthalpy 87 80

Claims (13)

(a) melting point of 151 ° C. (DSC, 2 K / min), (b) X-ray diffractograms reflected at 10.1, 12.0 and 19.8 (2θ), (c) an IR spectrum with maximum peaks at 3338 cm ⁻¹ , 1708 cm ^−1, and 1431 cm ⁻¹ , (d) ¹³ C-solid NMR spectrum with maximum peak at 107.9 ppm, 118.2 ppm and 135.0 ppm, (e) FIR spectra with maximum peaks at 264 cm ⁻¹ and 207 cm ⁻¹ , and (f) Raman spectra with maximum peaks at 3080 cm ⁻¹ , 1580 cm ^−1, and 122 cm ⁻¹ Thermodynamically stable variant of Lamatroban, comprising features selected from the group consisting of I. delete delete delete delete delete delete Thermodynamically stable variant I of Lamatroban according to claim 1, characterized in that the thermodynamically metastable variant of Ramatolovan is melted and rapidly cooled to form an amorphous phase, followed by stirring in an inert solvent to convert into a stable variant I. Seed crystal manufacturing method of the. The thermodynamically metastable variant of Ramatlovan was suspended in water or an inert organic solvent and inoculated with the seed of stable variant I, followed by the thermodynamically stable variant I of the resulting Lamatroban. A process for producing a thermodynamically stable form of latamide in accordance with claim 1, characterized in that it is converted until it contains less than 10%. delete delete Pharmaceuticals for treating thromboxane A2-mediated diseases or conditions selected from the group consisting of thrombosis, thromboembolism, ischemia, asthma and allergic reactions, comprising as an active ingredient the thermodynamically stable variant I of Lamatrovan according to claim 1 Composition. delete

Images